This K08 award will provide training for Dr. Huynh, under the guidance of Dr. Charles Hoover, Dr. Harold Goodis and Dr. Anahid Jewett to develop into an independent researcher. F. nucleatum, a gram-negative anaerobic organism, holds pathogenic roles in brain abscesses, pericarditis, as well as several oral diseases such as pulp infection, alveolar bone abscesses, and periodontal disease. F. nucleatum is one of the most commonly occurring species in the human gingival crevice and endodontic lesions. The interaction between bacterial species and the host defense mechanisms is considered to be the key element in determining the status of health and disease in the mouth. Dr. B.J. Shenker (1987) proposed a model of immunologic dysfunction occurring in the earliest stages of periodontal disease progression and followed by a period of depressed immune reactivity. The model is based on the observation that periodontal pathogens are capable of producing immunosuppressive factors. F. nucleatum has immunosuppressive activities, but the exact mechanism remains unclear. We have demonstrated that F. nucleatum aggregates and induces apoptotic cell death in peripheral blood mononuclear cells (PBMC). The exact pathway of induced PBMC cell death by F. nucleatum is unknown, however, we hypothesize that aggregation of PMBCs plays a critical role. To test this hypothesis, we set out to study the following specific aims: (1) to study the role of F. nucleatum adherence to immune cells in the induction of cell death, (2) to characterize adhesive molecules involved in aggregation of immune cells, (3) to elucidate the role of TNFa, FasL, and TRAIL in immune cell programmed cell death induced by F. nucleatum. Because certain F. nucleatum strains have resistance to various antibiotics such as amoxicillin and tetracycline, the findings of this proposal well allow us to understand F. nucleatum's mechanism of pathogenesis, and as a result, design more effective therapeutic strategies for periodontal and endodontal lesions in the future.